A central organizing hypothesis of the CTNA is that alcoholism, and perhaps the genetic vulnerability to alcoholism, involves altered functioning in glutamatergic circuits in the prefrontal cortex (PFC) and their limbic targets, notably the nucleus accumbens (NAc). The focus of Project is to carry out multi-disciplinary electrophysiological, molecular biological, and behavioral studies in laboratory animals to explore scientific aspects of this hypothesis that are closely related to CTNA Clinical Core Projects. First, we will characterize the effect of alcohol, after acute and chronic exposure, on glutamatergic circuitry within the PFC, and explore a role for endogenous 5-HT and opioidergic systems in these actions. Second, we will characterize the molecular mechanisms by which alcohol might alter glutamatergic transmission in the PFC and NAc. These latter studies will focus on a novel transcription factor, called deltaFosB, which we have shown to be induced in PFC and NAc by chronic alcohol administration and to regulate the expression of specific glutamate receptor subunits in those regions. The proposed studies will make use of state-of-the-art methodologies, including intracellular electrophysiological recording techniques, viral-mediated gene transfer inducible and brain region-specific transgenic mice, and a range of behavioral tests that measure alcohol responses in animal models. In many ways, the proposed studies in laboratory animals are defined by clinical phenomena, observed in normal humans and alcohol dependent patients, which have been defined by CTNA investigators over the past several years.